Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) is a synthetic diether phospholipid that is competitive with phosphatidylserine binding to the regulatory domain of protein kinase C (PKC). Our previous studies indicate that the selective inhibition of tumor cell growth by ET-18-OCH3 may be due to altered signal transduction mechanisms, including the inhibition of PKC. To further define the mechanism of action of ET-18-OCH3, we have used it to study the role of PKC in regulation of the transcription factor NF-kappa B, which is activated by diverse stimuli. In the 293.27.2 human kidney cell line, as in hematopoietic cells of all lineages, NF-kappa B is stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 alpha (IL-1 alpha). The response to either TNF-alpha or IL-1 alpha is synergistically enhanced by TPA. However, the regulatory mechanisms and signal transduction systems responsible for NF-kappa B activation in response to these different stimuli have not been determined in detail. We have used ET-18-OCH3 and auranofin, which inhibit PKC by different mechanisms, to assess the role of PKC in NF-kappa B activation. ET-18-OCH3 markedly inhibits TPA-induced NF-kappa B activation, as measured by HIV long terminal repeat-directed expression of beta-galactosidase. The IC50 for inhibition by ET-18-OCH3 is approximately 2 microM, a noncytotoxic concentration. Inhibition of TPA-induced NF-kappa B activation was dependent upon preincubation with ET-18-OCH3, and the drug was active at approximately 2 mol% of total cellular phospholipid. ET-18-OCH3 did not inhibit NF-kappa B activation by either TNF-alpha or IL-1 alpha, indicating that there are multiple distinct signal transduction pathways leading to activation of NF-kappa B. We have confirmed these results using auranofin, an antirheumatic drug that is a specific PKC inhibitor interacting with the catalytic domain. Like ET-18-OCH3, auranofin blocked NF-kappa B activation by TPA but not by TNF-alpha or IL-1 alpha. Also like the ether lipid, auranofin only partially blocked the synergy exhibited by TPA and TNF-alpha. To confirm the role of NF-kappa B in this response, we measured NF-kappa B by electrophoretic mobility shift assay. Both ET-18-OCH3 and auranofin inhibited cellular induction of the active NF-kappa B complex in response to TPA but not in response to TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:ET-18-OCH3 inhibits nuclear factor-kappa B activation by 12-O-tetradecanoylphorbol-13-acetate but not by tumor necrosis factor-alpha or interleukin 1 alpha. 758 18

A twofold increase in lymphocyte adherence to rat microvascular endothelial cells (EC) was achieved by incubating EC for 4 h with IL-1 alpha or dibutyryl-cAMP (stimulators of protein kinase A, PKA) and PMA (stimulator of protein kinase C, PKC). Monoclonal antibodies anti-CD11a, anti-CD18 (LFA-1) and anti-CD49d (VLA-4 alpha) significantly inhibited the increased lymphocyte binding to IL-1 alpha-induced EC, anti-CD18 and to a lesser extent anti-CD11a and anti-CD49d to dibutyryl-cAMP-induced EC, whereas only anti-CD11a and anti-CD18 monoclonal antibodies inhibited PMA-induced lymphocyte binding. These findings suggest that stimulation of PKA and PKC induces lymphocyte binding to EC via different adhesion molecules.
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PMID:Adhesion molecules involved in protein kinase A- and C-dependent lymphocyte adherence to microvascular endothelial cells. 768 Jan 40

The mRNAs coding for interleukin-1 alpha (IL-1 alpha) and IL-1 beta are constitutively transcribed but do not accumulate in human diploid fibroblasts and in fibrosarcoma cells. Treatment of these cells with tumor necrosis factor (TNF) induces accumulation of IL-1 mRNA by an unknown mechanism. This induction of IL-1 mRNA was investigated in HT-1080 cells. The induction was quite fast, with maximum levels of IL-1 alpha and beta mRNA reached 4 h after addition of TNF. Nuclear run-off experiment showed that TNF did not increase the rate of transcription of IL-1 mRNA. This mRNA was apparently unstable in untreated cells, but it accumulated in cycloheximide-treated cells. Phorbol esters induced IL-1 mRNA, suggesting that activation of protein kinase C was responsible for the accumulation of this mRNA. This hypothesis was confirmed by experiments with the PKC inhibitors staurosporine and calphostin C, which prevented the induction of IL-1 mRNA by TNF and accelerated the decay of this mRNA in cells pretreated with TNF. Both IL-1 alpha and IL-1 beta were detected in TNF-treated cells by Western blot analysis and enzyme-linked immunosorbent assay. These results indicate that the TNF-mediated induction of IL-1 can be entirely accounted for by stabilization of this mRNA.
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PMID:Tumor necrosis factor increases stability of interleukin-1 mRNA by activating protein kinase C. 768 Oct 61

In human umbilical endothelial cells, treatment with tumor necrosis factor (TNF)-alpha stimulated the production of cell-associated interleukin (IL)-1 alpha. Combined treatment of human umbilical endothelial cells with TNF-alpha and the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed the TNF-alpha-induced production of IL-1 alpha. However, concentrations of 6-keto-prostaglandin F1 alpha in the conditioned medium were increased to a greater extent by combined treatment with TNF-alpha and TPA than by single treatment with TNF-alpha or TPA. Pretreatment with TPA for 15 min was enough to suppress the TNF-alpha-induced IL-1 alpha production. Pretreatment for 15 min with other PKC activators such as aplysiatoxin or teleocidin, also inhibited the TNF-alpha-induced IL-1 alpha production. Stimulation of cell-associated IL-1 alpha production by IL-1 beta or lipopolysaccharide was also inhibited by pretreatment with the PKC activator TPA, aplysiatoxin or teleocidin. However, treatment with the protein kinase inhibitor 1-(5-isoquinoline-sulphonyl)-2- methylpiperazine dihydrochloride (H-7) did not block the inhibitory effect of TPA, aplysiatoxin or teleocidin on the cell-associated IL-1 alpha production stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide, although the PKC activator-induced stimulation of 6-keto-prostaglandin F1 alpha production was counteracted by H-7 treatment. The present work indicates that the production of cell-associated IL-1 alpha stimulated by TNF-alpha, IL-1 beta or lipopolysaccharide is inhibited by treatment with TPA, aplysiatoxin or teleocidin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppression of interleukin-1 alpha production by protein kinase C activators in human vascular endothelial cells. 785 98

Characteristics of the cytokine response in resident mouse macrophages to certain Gram-positive and Gram-negative bacteria have been investigated by monitoring the expression of mRNA encoding interleukin-1 alpha and -beta (IL-1 alpha/beta) and tumor necrosis factor-alpha (TNF-alpha). Expression of these cytokine mRNAs occurred within 30-60 min. Both the flavonoid quercetin and phloretin inhibited the expression of IL-1 alpha/beta as well as TNF-alpha mRNA, with quercetin being more potent than phloretin and TNF-alpha expression somewhat more sensitive than that of IL-1 alpha/beta. Expression of all three cytokine mRNAs was also inhibited by prostaglandin E2, with an IC50 of > 1 microM, but not by the phosphodiesterase inhibitor pentoxifylline, although lipopolysaccharide-induced expression of TNF-alpha mRNA was inhibited. Down-regulation of phorbol ester-sensitive isoforms of protein kinase C had virtually no effect on the cytokine response to bacteria, and treatment of resting macrophages with phorbol ester did not cause expression of any of the cytokine mRNAs investigated. Among protein phosphatase inhibitors, cyclosporin A caused extensive inhibition of bacteria-induced expression of both IL-1 alpha/beta and TNF-alpha mRNA, while okadaic acid in itself caused selective induction of TNF-alpha, but not IL-1 alpha/beta mRNA, with a sharp peak at 0.3 microM concentration. At higher concentrations of okadaic acid, at which protein/phosphatase 2B/calcineurin would also be inhibited, the induction was completely reversed. This suggests that critical phosphorylation events, counteracted by one or more okadaic acid-sensitive protein phosphatase(s), and a dephosphorylation event carried out by a cyclosporin-sensitive protein phosphatase are both necessary for transcriptional activation of the TNF-alpha gene.
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PMID:Cyclosporin-sensitive expression of cytokine mRNA in mouse macrophages responding to bacteria. 787 67

We have investigated the possibility of a protein kinase participating in the signal transduction mechanisms of the interleukin-1 (IL-1) type I receptor (IL-1RI). Our data show that a protein kinase was co-precipitated with the IL-1RI from the two murine T helper cell lines D10N and EL-4. The kinase activity was detected in an in vitro kinase assay performed with the immuno beads in the presence of exogenous substrates. IL-1 treatment of the cells resulted in a rapid activation of this protein kinase in a concentration-dependent manner. Both forms of IL-1, IL-1 alpha and IL-1 beta, induced this kinase activity, whereas the IL-1 receptor antagonist (IL-1ra) was inactive. In excess IL-1ra competitively antagonized IL-1 stimulation. In the in vitro kinase assay the exogenous substrates myelin basic protein and histone H1 were phosphorylated, whereas casein or heat-shock protein HSP27 were not accepted, reflecting a certain selectivity of this protein kinase. The IL-1RI co-precipitable protein kinase showed a serine/threonine specificity and was inhibited by staurosporine, but not by inhibitors specific for protein tyrosine kinase or protein kinase C. These results show that a serine/threonine protein kinase directly interacts with the IL-1RI at the plasma membrane level of T helper cells forming a novel type of IL-1 inducible signaling complex. This protein kinase may resemble the link coupling the plasma membrane IL-1 receptor to cytosolic downstream elements in the IL-1 signaling pathway.
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PMID:Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells. 802 18

We investigated the signal transduction pathways leading to the 12-O-tetradecanoylphorbol-13-acetate (TPA)- and interleukin-1 alpha (IL-1)-induced IL-1 alpha mRNA in mouse keratinocytes. Induction of IL-1 alpha mRNA by TPA or IL-1 alpha was followed by increases in cell-associated IL-1 alpha protein measured by enzyme-linked immunosorbent assay. Although protein kinase C (PKC) was involved in TPA-induced IL-1 alpha mRNA, down-regulation of PKC did not block the induction of this gene by TPA. The autocrine induction of IL-1 alpha was not mediated through PKC or cAMP. IL-1 alpha did activate mitogen-activated protein kinase. Genistein, a tyrosine kinase inhibitor, blocked both IL-1 alpha-induced mitogen-activated protein kinase activation as well as IL-1 alpha mRNA expression. Genistein, at an unsaturating dose, plus a serine/threonine kinase inhibitor, H7, completely blocked the autocrine induction of IL-1 alpha suggesting that expression of this gene is regulated by tyrosine kinase(s) in combination or independently with serine/threonine kinase(s). In addition, both TPA and IL-1 alpha caused increases not only in the phosphorylation of c-Jun and c-Fos protein but also in the transactivating activity of AP-1 nuclear transcription factor. Neither TPA nor IL-1 alpha induced NF-kappa B binding activity, as assessed by electrophoretic mobility shift analysis. This study suggests that the activation of AP-1 may be a common event through which TPA and IL-1 alpha induce IL-1 alpha mRNA.
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PMID:Signal transduction pathway(s) involved in phorbol ester and autocrine induction of interleukin-1 alpha mRNA in murine keratinocytes. 802 56

Microglia, the resident macrophages of the brain, secrete a number of mediators involved in neural-immune function. The cytokines, IL-1 alpha and TNF alpha, are two such factors which are stored as inactive precursor molecules requiring post-translational proteolytic processing prior to release. From investigations of second messenger pathways involved in regulating the secretion of these cytokines, we have demonstrated that the PKC inhibitor, H-7, blocks the induction of TNF alpha secretion induced by LPS. In contrast, H-89 and HA-1077, inhibitors of cyclic nucleotide-dependent protein kinases (PKA and PKG), did not alter LPS-stimulation of TNF alpha release. Consistent with these observations, the weak PKC activator, mezerein, induced TNF alpha secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1 alpha secretion and H-7 potentiated IL-1 alpha release. In the case of the protein phosphatase inhibitor, okadaic acid, secretion of both cytokines was induced, indicating that protein phosphorylation is important for the induction of cytokine secretion but only in the case of TNF alpha is PKC involved. In the case of IL-1 alpha, a tonic inhibitory regulation involving PKC activation may be present. We therefore conclude that alterations in phosphorylation-dephosphorylation cycles may be important triggers in the switching of microglial cellular function from a resting to an activated state.
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PMID:Differential regulation of IL-1 alpha and TNF alpha release from immortalized murine microglia (BV-2). 806 28

To determine the effects of the pineal hormone melatonin on human monocytes, human monocytes were activated by different concentrations of melatonin. Above the activation threshold of 5 x 10(-11) M, melatonin was able to induce the cytotoxicity of human monocytes, the secretion of IL-1, and the production of reactive oxygen intermediates. Melatonin and LPS seemed to have a synergistic effect on human monocyte activation. Indeed, below their respective monocyte activation threshold (5 x 10(-11) M and 0.625 ng/ml), melatonin (10(-12) M) in association with LPS (0.2 ng/ml) was able to induce cytotoxicity, IL-1 secretion, and reactive oxygen intermediates production. Melatonin alone at 10(-12) M or LPS alone at 0.2 ng/ml did not activate monocytes. Furthermore, melatonin was able to prime the monocytes for a subsequent activation by LPS. When monocytes were activated by LPS (0.25 ng/ml) at the time that they were plated and then activated by melatonin (10(-12) M) 8 h later, no IL-1 secretion and no cytotoxicity were detected. However, when the cells were first activated by melatonin (10(-12) M), and then 8 h later by LPS (0.25 ng/ml), IL-1 secretion and monocyte cytotoxicity were observed. Above its monocyte activation threshold, melatonin induces both cell-associated IL-1 alpha and IL-1 beta activities. Below this activation threshold, i.e., at 10(-12) M, melatonin does not induce the cell-associated IL-1 alpha and IL-1 beta activities, but does induce the mRNA for both IL-1 (alpha and beta). It seems that melatonin activates monocytes through protein kinase C. These data suggest that melatonin activates monocytes and induces their cytotoxic properties, along with the IL-1 secretion.
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PMID:Activation of human monocytes by the pineal hormone melatonin. 807 74

An important challenge in the field of auto-immune diseases, bone marrow and organ transplantation is the control of T-lymphocyte activation. To gain more insight into the in vitro correlation of immunosuppression, we investigated the effects of cyclosporin A (CSA) and two other metabolic inhibitors on cytokine secretion and T-cell proliferation. Secretion of TNF-alpha and GM-CSF was much more resistant to metabolic inhibitors than proliferation or synthesis of IL-1 alpha or IL-2. Moreover, our data suggested that the regulation of IL-1 alpha production in T-cells was CSA and protein kinase C (PKC)-dependent, as opposed to monocytes regulation. The receptivity to the epithelial cell-derived cytokine IL-7, associated either with antigen-dependent or independent triggering, was almost similarly inhibited by cyclosporin A, forskolin or PKC inhibitor, in sharp contrast to IL-2 receptivity. In this latter case, CD28+ IL-2 stimulation was more sensitive to both forskolin and PKC inhibition than that of CD2 or CD3+ IL-2. With regard to CSA effects, limiting dilution analysis provided evidence for some heterogeneity at the clonal level. This strongly suggested that T-cell functional monitoring at the population level does not truly reflect the actual immunosuppression. Additional experiments are required to evaluate the sensitivity to metabolic inhibitors of T-lymphocyte activation via the natural ligands of CD2 and CD28.
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PMID:Differential immuno-suppressive effects of metabolic inhibitors on T-lymphocyte activation. 810 Apr 56


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